New therapeutic agents are urgently needed for the treatment of sickle cell disease (SCD), the world's most common genetic disease. Our long-term goal is to develop a botanical drug for use in children that prevents the inexorable progression of SCD. SCD affects approximately 100,000 people in the United States and millions worldwide. It kills more children in Africa than HIV, but while HIV commands vast attention from the international community, SCD is virtually invisible. In the US, those with SCD have an average mortality in their 40s and an estimated aggregate cost of medical care in excess of $1.4 billion per year. In less developed countries, 80% of children with SCD die before the age of five. The only FDA approved disease-modifying drug for use in SCD is the anti-cancer drug hydroxyurea, which has serious side effects and is only approved for use in adults. SCD results from a mutation in the -globin gene (Hb S), a variant of Hb A, the common adult hemoglobin. When deoxygenated, Hb S polymerizes, forming long polymers that deform the biconcave red blood cells (RBCs) into rigid, adherent, sickle-shaped cells. The rigid sickled RBCs are easily trapped in the microvasculature, blocking blood flow to tissues and organs with resultant ischemic tissue damage. Best supportive therapies for SCD include folic acid for anemia, penicillin to prevent infections, pneumococcal and influenza vaccinations, pain medication, and intravenous injection of fluids. Chronic transfusion therapy can modify the course of the disease, but hyperviscosity, alloimmune reaction, infection, and iron overload are just a few of the complications of transfusion therapy. Bone marrow transplants can cure SCD, but the morbidity and mortality of the procedure, coupled with difficulty in finding a donor match and the cost of the procedure, leave this an uncommon treatment option. We propose a Phase I dose escalation trial in adults with SCD to obtain an initial safety profile and explore possible effective oral doses of a botanical drug that inhibits RBCs from sickling. The rationale for the proposed research is that inhibiting RBCs from sickling, the hallmark of the disease, will reduce anemia, reduce vasoocclusion and pain, reduce cumulative organ damage, and reduce vascular inflammation caused by the adherence of the RBCs to endothelial and white blood cells.